Salts of hmg-coa reductase inhibitors and use thereof

Abstract

The present invention relates to salts of HMG CoA reductase inhibitors, and in particular, rosuvastatin amine salts and their use as intermediates in the preparation of rosuvastatin calcium.

1 . Amine salts of rosuvastatin of Formula I 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with the proviso that amine is not ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine. 
   
   
       2 . The amine salts of rosuvastatin of  claim 1 , having purity above 99% and diastereomeric impurity less than 0.5%. 
   
   
       3 . The compound according to  claim 2 , wherein the purity is more than 99.5% and diastereomeric impurity less than 0.25%. 
   
   
       4 . The compound according to  claim 3 , wherein the purity is more than 99.75% and diastereomeric impurity less than 0.15%. 
   
   
       5 . A process for the preparation of amine salts of rosuvastatin of Formula I 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with the proviso that amine is not ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine, 
     the process comprising:
 a) treating rosuvastatin of Formula II 
 
     
       
         
         
             
             
         
       
        with an amine of Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with a proviso that the amine is not selected from ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine; and 
       b) isolating the amine salt of rosuvastatin of Formula I. 
     
   
   
       6 . (canceled) 
   
   
       7 . A process for preparation of amorphous or crystalline rosuvastatin calcium of Formula IIa from amine salt of Formula I, 
     
       
         
         
             
             
         
       
     
     wherein the process comprises of
 a) treating an amine salt of Formula I, 
 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with a proviso that the amine is not selected from ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine, with an acid;
 b) optionally isolating rosuvastatin acid or a lactone thereof; 
 c) adding a base and calcium ions; 
 d) isolating amorphous rosuvastatin calcium; and 
 e) optionally converting amorphous rosuvastatin calcium to crystalline rosuvastatin calcium. 
 
   
   
       8 . A process for the preparation of amorphous rosuvastatin calcium from amine salt rosuvastatin of Formula I 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with a proviso that the amine is not selected from ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine, 
     the process comprising
 a) treating an amine salt of rosuvastatin with a base and a calcium ions; and 
 b) isolating the amorphous rosuvastatin calcium from the reaction mass. 
 
   
   
       9 . Amorphous rosuvastatin calcium prepared by a process according to  claims 7  and  8  having a purity of at least above 99% having less than 0.5% of diastereomeric impurity. 
   
   
       10 . A process for preparation of amorphous or crystalline rosuvastatin magnesium of 
     
       
         
         
             
             
         
       
     
     from amine salt of Formula I, 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with a proviso that the amine is not selected from ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine, 
     wherein the process comprises:
 a) treating an amine salt of Formula I with an acid; 
 b) optionally isolating rosuvastatin acid or a lactone thereof; 
 c) adding a base and magnesium ions; 
 d) isolating crystalline rosuvastatin magnesium; and 
 e) optionally converting crystalline rosuvastatin magnesium to amorphous rosuvastatin magnesium. 
 
   
   
       11 . A process according to  claim 10  wherein the acid is selected from inorganic mineral acids or organic acids. 
   
   
       12 . A process for the preparation of amorphous rosuvastatin magnesium from amine salt of rosuvastatin of Formula I 
     
       
         
         
             
             
         
       
     
     or solvate, hydrate, crystalline or amorphous form thereof, in which the amine residue has a Formula NR 1 R 2 R 3  (wherein independently R 1 , R 2  and R 3  are H, straight or branched chain C 1-15  alkyl or hydroxyalkyl, C 3-10  single or fused ring optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, alkylcycloalkyl, or independently R 1 , R 2  and R 3  combine with each other to form a C 3-7  membered cycloalkyl ring or heterocyclic residue containing one or more heteroatoms), with a proviso that the amine is not selected from ammonia, methylamine, ethylamine, diethanolamine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-methoxybenzylamine, 
     which comprises:
 a) treating an amine salt of rosuvastatin with a base and a magnesium ions; and 
 b) isolating the crystalline rosuvastatin magnesium from the reaction mass. 
 
   
   
       13 . Highly pure rosuvastatin calcium or rosuvastatin magnesium in crystalline or amorphous form thereof having purity of at least above 99.5% and diastereomeric impurity less than 0.25%. 
   
   
       14 .- 23 . (canceled) 
   
   
       24 . A pharmaceutical composition comprising amine salts rosuvastatin according to  claim 1 . 
   
   
       25 . A method of treating disease conditions wherein HMG-CoA is implicated, which comprises of administering to a mammal in need thereof a therapeutically effective amount of amine salt of rosuvastatin according to  claim 1 .